| Autor: |
Cara E. Toscan, Hannah McCalmont, Amir Ashoorzadeh, Xiaojing Lin, Zhe Fu, Louise Doculara, Hansen J. Kosasih, Roxanne Cadiz, Anthony Zhou, Sarah Williams, Kathryn Evans, Faezeh Khalili, Ruilin Cai, Kristy L. Yeats, Andrew J. Gifford, Russell Pickford, Chelsea Mayoh, Jinhan Xie, Michelle J. Henderson, Toby N. Trahair, Adam V. Patterson, Jeff B. Smaill, Charles E. de Bock, Richard B. Lock |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Blood Cancer Journal, Vol 14, Iss 1, Pp 1-13 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2044-5385 |
| DOI: |
10.1038/s41408-024-01180-x |
| Popis: |
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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